The present invention relates to a process for preparing valproic acid useful for various uses including medicines.
As a process for preparing valproic acid, there have hitherto been known (a) a process using 4-hydroxy-heptane as a starting material, (b) a process using cyanoacetic acid ester as a starting material, (c) a process using a malonic acid ester as a starting material, and the like. However, the above-mentioned processes are unsatisfactory in industrial scale since the yields of valproic acid are about 70% by mole in all the processes (a) to (c). Moreover, in the process (a), reagents such as Grignard reagent and sodium prussiate, which are expensive and must be handled carefully, must be employed, in the process (b), the reaction conditions are very severe, and in the process (c), expensive starting materials are required.
Japanese Unexamined Patent Publication (Tokkyo Kokai) No. 156638/1985, as an improved process of the above-mentioned processes (a) to (c), has disclosed a process for preparing valproic acid which comprises:
(1) reacting an acetoacetic acid ester with an allyl halide to give a 2,2-diallyl acetoacetic acid ester,
(2) reacting an alcohol with the 2,2-diallyl acetoacetic acid ester to give a diallyl acetic acid ester, and
(3) hydrolyzing the diallyl acetic acid ester to give a diallyl acetic acid and reducing the diallyl acetic acid, or
(3)' reducing the diallyl acetic acid ester to give a valproic acid ester and hydrolyzing the valproic acid ester.
The process disclosed in Tokkyo Kokai No. 156638/1985 has an advantage that valproic acid can be easily produced from cheap starting materials, but in the step (3) or (3)', an .alpha.-propyl-.beta.-ethyl-acrylic ester is produced as a by-product. Although the amount of the by-product is small, the by-product remarkably lowers the quality as medicines since it cannot be easily removed with usual purifications. Accordingly, valproic acid obtained by the abovementioned process requires an additive step for removing the by-product.
An object of the present invention is to provide an industrially excellent process for preparing valproic acid improving the above-mentioned disadvantage.
The above and other objects of the present invention will become apparent from the description hereinafter.